title: SIRT3 opposes reprogramming of cancer cell metabolism through HIF1α destabilization.
abstract: Tumor cells exhibit aberrant metabolism characterized by high glycolysis even in the presence of oxygen. This metabolic reprogramming, known as the Warburg effect, provides tumor cells with the substrates required for biomass generation. Here, we show that the mitochondrial NAD-dependent deacetylase SIRT3 is a crucial regulator of the Warburg effect. Mechanistically, SIRT3 mediates metabolic reprogramming by destabilizing hypoxia-inducible factor-1α (HIF1α), a transcription factor that controls glycolytic gene expression. SIRT3 loss increases reactive oxygen species production, leading to HIF1α stabilization. SIRT3 expression is reduced in human breast cancers, and its loss correlates with the upregulation of HIF1α target genes. Finally, we find that SIRT3 overexpression represses glycolysis and proliferation in breast cancer cells, providing a metabolic mechanism for tumor suppression.
authors.affiliation: Department of Pathology, The Paul F. Glenn Labs for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lydia W S
authors.initials: LW
authors.lastname: Finley
authors.forename: Arkaitz
authors.initials: A
authors.lastname: Carracedo
authors.forename: Jaewon
authors.initials: J
authors.lastname: Lee
authors.forename: Amanda
authors.initials: A
authors.lastname: Souza
authors.forename: Ainara
authors.initials: A
authors.lastname: Egia
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: Paula I
authors.initials: PI
authors.lastname: Moreira
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Cardoso
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D015151:Immunoblotting; D008297:Male; D055432:Metabolomics / Q000379:methods*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D008819:Mice, Nude; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055550:Protein Stability; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D014183:Transplantation, Heterologous
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017382:Reactive Oxygen Species; C525046:Sirt3 protein, mouse; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D005947:Glucose